1. Mesocorticolimbic circuits are impaired in chronic cocaine users as demonstrated by resting-state functional connectivity Cocaine dependent individuals manifest alterations in reward functioning that may relate to changes induced by cocaine or to pre-existing differences related to vulnerability to addiction. The circuit level manifestations of these drug-induced plastic changes and predispositions to drug dependence are poorly understood in preclinical models and virtually unknown in human drug dependence. Using whole-brain resting-state fMRI connectivity analysis with 'seed voxels'placed within individual nodes of the MCL system, we report network-specific functional connectivity strength decreases in cocaine users within distinct circuits of the system, including between ventral tegmental area (VTA) and a region encompassing thalamus/lentiform nucleus/nucleus accumbens, between amygdala and medial prefrontal cortex (mPFC), and between hippocampus and dorsal mPFC. Further, regression analysis on regions showing significant functional connectivity decrease in chronic cocaine users revealed that the circuit strength between VTA and thalamus/lentiform nucleus/nucleus accumbens was negatively correlated with years of cocaine use. This is the first evidence of circuit-related changes in human cocaine dependence and is consistent with the range of cognitive and behavioral disruptions seen in cocaine dependence. As potential circuit level biomarkers of cocaine dependence, these circuit alterations may be usefully applied in treatment development and monitoring treatment outcome. (NeuroImage 53:593-601, 2010) 2. Lower glutamate levels in rostral anterior cingulate of chronic cocaine users - A H-MRS study Previous studies have shown significantly lower metabolism and functional activity in the anterior cingulate cortex (ACC) of human cocaine addicts. The present study examined whether this ACC hypoactivity is associated with altered glutamate (Glu), the primary excitatory neurotransmitter in the central nervous system (CNS), which has been recently implicated in drug addiction. Participants comprised 14 chronic cocaine addicts and 14 matched healthy volunteers who were examined using (1)H magnetic resonance spectroscopy at 3 T. The concentrations of Glu as well as N-acetyl aspartate (NAA), total creatine (tCr), choline-containing compounds (tCho), and myo-inositol (Ins) were estimated from both groups. Glu/tCr was significantly lower in chronic cocaine users compared to control subjects and was significantly correlated with years of cocaine use. Glu/tCr was also positively correlated with NAA/tCr. NAA/tCr significantly decreased with age but was not significantly different between the two groups. These findings suggest a metabolic/neurotransmitter dysregulation associated with cocaine addiction and support a possible therapeutic intervention strategy aimed at normalizing the Glu transmission and function in the treatment of cocaine addiction. (Psychiatry Res 174:171-176, 2009) 3. A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction Whole-genome searches have identified nicotinic acetylcholine receptor alpha5-alpha3-beta4 subunit gene variants that are associated with smoking. How genes support this addictive and high-risk behavior through their expression in the brain remains poorly understood. Here we show that a key alpha5 gene variant Asp398Asn is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, such that the "risk allele" decreases the intrinsic resting functional connectivity strength in this circuit. Importantly, this effect is observed independently in nonsmokers and smokers, although the circuit strength distinguishes smokers from nonsmokers, predicts addiction severity in smokers, and is not secondary to smoking per se, thus representing a trait-like circuitry biomarker. This same circuit is further impaired in people with mental illnesses, who have the highest rate of smoking. Identifying where and how brain circuits link genes to smoking provides practical neural circuitry targets for new treatment development. (Proc Natl Aced Sci USA. 107, 13509-13514, 2010) 4. Automated brain tissue segmentation based on fractional signal mapping from inversion recovery Look-Locker acquisition Most current automated segmentation methods are performed on T(1)- or T(2)-weighted MR images, relying on relative image intensity that is dependent on other MR parameters and sensitive to B(1) magnetic field inhomogeneity. Here, we propose an image segmentation method based on quantitative longitudinal magnetization relaxation time (T(1)) of brain tissues. Considering the partial volume effect, fractional volume maps of brain tissues (white matter, gray matter, and cerebrospinal fluid) were obtained by fitting the observed signal in an inversion recovery procedure to a linear combination of three exponential functions, which represents the relaxations of each of the tissue types. A Look-Locker acquisition was employed to accelerate the acquisition process. The feasibility and efficacy of this proposed method were evaluated using simulations and experiments. The potential applications of this method in the study of neurological disease as well as normal brain development and aging are discussed. (NeuroImage 52, 1347-1354, 2010) 5. Effects of CBV, CBF, and blood-brain barrier permeability on accuracy of PASL and VASO measurement Cerebral blood flow, cerebral blood volume (CBV), and water permeability through blood-brain barrier are important hemodynamic parameters in brain physiology. In the current work, the biophysical effects of CBV on pulsed arterial spin labeling and permeability on vascular-space occupancy signals are evaluated using a general two-compartment model. The dependence of these effects on the T(1) at various field strengths is also assessed by simulations. Results indicate that CBV has negligible to small influences on pulsed arterial spin labeling signal (<6.6% at 3 T) and permeability effects are negligible on vascular-space occupancy signal (<0.1% at 3 T) under normal physiologic conditions. In addition, CBV effect on pulsed arterial spin labeling is further diminished at high field strengths, but residual blood contamination in vascular-space occupancy signal may be enhanced at high fields due to the reduced difference between extra- and intravascular T(1) values. (Magn Reson Med, 2010, 63: 601-608) 6. Unbiased Group-Wise Image Registration: Applications in Brain Fiber Tract Atlas Construction and Functional Connectivity Analysis We propose an unbiased implicit-reference group-wise (IRG) image registration method and demonstrate its applications in the construction of a brain white matter fiber tract atlas and the analysis of resting-state functional MRI (fMRI) connectivity. Most image registration techniques pair-wise align images to a selected reference image and group analyses are performed in the reference space, which may produce bias. The proposed method jointly estimates transformations, with an elastic deformation model, registering all images to an implicit reference corresponding to the group average. The unbiased registration is applied to build a fiber tract atlas by registering a group of diffusion tensor images. Compared to reference-based registration, the IRG registration improves the fiber track overlap within the group. After applying the method in the fMRI connectivity analysis, results suggest a general improvement in functional connectivity maps at a group level in terms of larger cluster size and higher average t-scores. (J Med Syst, 2010, in press)